The goal of our proposal is to bring new insights and enabling technology to the principles and practice of handling proteins and peptides as drugs and their formulation as polymer/protein microspheres. With the world-wide demand for innovative protein therapeutics growing at 30% per year, and a market penetration for protein therapeutics estimated to reach $40 billion worldwide by 2018, effective drug delivery becomes the next significant obstacle. In this proposal we are taking a quantitative approach that expands on the existing fund of knowledge already present in this established, yet not fully optimized, field of polymer-based drug and agent delivery. We are following a relatively straightforward research design -single particle studies (experiment and theory) followed by bulk suspension characterization of composition, structure, and function. By studying individual droplets and individual components serially in SA1, the plan is to obtain crucial measurements not easily obtained by any other method, i.e., the dynamic concentration of each component in the droplet, correlated with events such as precipitation, viscous changes, microstructural inclusions, and time for hardening. Microsphere hydrolysis and protein release are also measurable on single microspheres. Specific Aim 2 then looks to correlate these measurements, and modeling with the physical and chemical characteristics and properties of the microspheres as bulk suspensions. And SA3 completes the investigation by directly relating microsphere protein release and protein function, to processs and compositional variables and developed microsphere microstructure. New innovation is developed in SA4 where we will form glassified protein nanospheres for improved protein stability and dispersion. These data will be crucial for developing a sustained release system for conotoxins (SA5) and thus address the important problem of pain control. Upon completion of this project then we aim to provide a more detailed recipe for specific formulations of protein drugs, and in the process, to be able to offer a more complete design engineering methodology, and enabling technology for microsphere brmulation, especially for environment-sensitive proteins and peptides.